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. 2014 Dec 2;30(6):903–912. doi: 10.1007/s12264-014-1481-9

Alterations of natural killer cells in traumatic brain injury

Xiao-Dong Kong 1,2, Sheng Bai 1, Xin Chen 1, Hui-Jie Wei 1, Wei-Na Jin 1, Min-Shu Li 1, Yaping Yan 1, Fu-Dong Shi 1,3,✉
PMCID: PMC5562566  PMID: 25446874

Abstract

To investigate the relationship between natural killer (NK) cells and traumatic brain injury (TBI), we tracked an established phenotype of circulating NK cells at several time points in patients with different grades of TBI. In serial peripheral blood samples, NK cells were prospectively measured by flow cytometry of CD3− CD56+ lymphocytes. Compared to healthy controls, TBI patients had reductions in both the percentage and the absolute number of NK cells. Furthermore, the magnitude of NK cell reduction correlated with the degree of TBI severity at several time points. That is, NK cell population size was independently associated with lower Glasgow Coma Scale scores. In addition, at some time points, a positive correlation was found between the NK cell counts and Glasgow Outcome Scale scores. Our results indicate that TBI induces a reduction in the number of NK cells, and the magnitude of the reduction appears to parallel the severity of TBI.

Keywords: natural killer cells, traumatic brain injury, central nervous system, immunity

References

  • [1].Ghajar J. Traumatic brain injury. Lancet. 2000;356:923–929. doi: 10.1016/S0140-6736(00)02689-1. [DOI] [PubMed] [Google Scholar]
  • [2].Schneider HJ, Kreitschmann-Andermahr I, Ghigo E, Stalla GK, Agha A. Hypothalamopituitary dysfunction following traumatic brain injury and aneurysmal subarachnoid hemorrhage: a systematic review. JAMA. 2007;298:1429–1438. doi: 10.1001/jama.298.12.1429. [DOI] [PubMed] [Google Scholar]
  • [3].Chen X, Zhang KL, Yang SY, Dong JF, Zhang JN. Glucocorticoids aggravate retrograde memory deficiency associated with traumatic brain injury in rats. J Neurotrauma. 2009;26:253–260. doi: 10.1089/neu.2007.0504. [DOI] [PubMed] [Google Scholar]
  • [4].Maas AI, Stocchetti N, Bullock R. Moderate and severe traumatic brain injury in adults. Lancet Neurol. 2008;7:728–741. doi: 10.1016/S1474-4422(08)70164-9. [DOI] [PubMed] [Google Scholar]
  • [5].Wang SY, Li YH, Chi GB, Xiao SY, Ozanne-Smith J, Stevenson M, et al. Injury-related fatalities in China: an under-recognised public-health problem. Lancet. 2008;372:1765–1773. doi: 10.1016/S0140-6736(08)61367-7. [DOI] [PubMed] [Google Scholar]
  • [6].Fabregas N, Torres A. Pulmonary infection in the brain injured patient. Minerva Anestesiol. 2002;68:285–290. [PubMed] [Google Scholar]
  • [7].Piek J, Chesnut RM, Marshall LF, van Berkum-Clark M, Klauber MR, Blunt BA, et al. Extracranial complications of severe head injury. J Neurosurg. 1992;77:901–907. doi: 10.3171/jns.1992.77.6.0901. [DOI] [PubMed] [Google Scholar]
  • [8].Meisel C, Schwab JM, Prass K, Meisel A, Dirnagl U. Central nervous system injury-induced immune deficiency syndrome. Nat Rev Neurosci. 2005;6:775–786. doi: 10.1038/nrn1765. [DOI] [PubMed] [Google Scholar]
  • [9].Wong CH, Jenne CN, Lee WY, Leger C, Kubes P. Functional innervation of hepatic iNKT cells is immunosuppressive following stroke. Science. 2011;334:101–105. doi: 10.1126/science.1210301. [DOI] [PubMed] [Google Scholar]
  • [10].Shi FD, Ransohoff R. Nature killer cells in the central nervous system. In: Lotze MT, Thomson AW, editors. Natural Killer Cells. London: Academic Press; 2010. pp. 373–384. [Google Scholar]
  • [11].Shi F D, Ljunggren HG, La Cava A, Van Kaer L. Organ-specific features of natural killer cells. Nat Rev Immunol. 2011;11:658–671. doi: 10.1038/nri3065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [12].Shi F D, Wang HB, Li H, Hong S, Taniguchi M, Link H, et al. Natural killer cells determine the outcome of B cell-mediated autoimmunity. Nat Immunol. 2000;1:245–251. doi: 10.1038/79792. [DOI] [PubMed] [Google Scholar]
  • [13].Shi F D, Ljunggren HG, Sarvetnick N. Innate immunity and autoimmunity: from self-protection to self-destruction. Trends Immunol. 2001;22:97–101. doi: 10.1016/S1471-4906(00)01821-4. [DOI] [PubMed] [Google Scholar]
  • [14].Hao J, Liu R, Piao W, Zhou Q, Vollmer TL, Campagnolo DI, et al. Central nervous system (CNS)-resident natural killer cells suppress Th17 responses and CNS autoimmune pathology. J Exp Med. 2010;207:1907–1921. doi: 10.1084/jem.20092749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [15].Forel JM, Chiche L, Thomas G, Mancini J, Farnarier C, Cognet C, et al. Phenotype and functions of natural killer cells in critically-ill septic patients. PLoS One. 2012;7:e50446. doi: 10.1371/journal.pone.0050446. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [16].Mrakovcic-Sutic I, Tokmadzic VS, Laskarin G, Mahmutefendic H, Lucin P, Zupan Z, et al. Early changes in frequency of peripheral blood lymphocyte subpopulations in severe traumatic brain-injured patients. Scand J Immunol. 2010;72:57–65. doi: 10.1111/j.1365-3083.2010.02407.x. [DOI] [PubMed] [Google Scholar]
  • [17].Wolach B, Sazbon L, Gavrieli R, Broda A, Schlesinger M. Early immunological defects in comatose patients after acute brain injury. J Neurosurg. 2001;94:706–711. doi: 10.3171/jns.2001.94.5.0706. [DOI] [PubMed] [Google Scholar]
  • [18].Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet. 1974;2:81–84. doi: 10.1016/S0140-6736(74)91639-0. [DOI] [PubMed] [Google Scholar]
  • [19].Brain Trauma F. American Association of Neurological S, Congress of Neurological S. Guidelines for the management of severe traumatic brain injury. J Neurotrauma. 2007;24(Suppl1):S1–106. doi: 10.1089/neu.2007.9999. [DOI] [PubMed] [Google Scholar]
  • [20].Marshall LF, Marshall SB, Klauber MR, Van Berkum Clark M, Eisenberg H, Jane JA, et al. The diagnosis of head injury requires a classification based on computed axial tomography. J Neurotrauma. 1992;9(Suppl1):S287–292. [PubMed] [Google Scholar]
  • [21].Marion DW, Penrod LE, Kelsey SF, Obrist WD, Kochanek PM, Palmer AM, et al. Treatment of traumatic brain injury with moderate hypothermia. N Engl J Med. 1997;336:540–546. doi: 10.1056/NEJM199702203360803. [DOI] [PubMed] [Google Scholar]
  • [22].Cooper DJ, Rosenfeld JV, Murray L, Arabi YM, Davies AR, D’Urso P, et al. Decompressive craniectomy in diffuse traumatic brain injury. N Engl J Med. 2011;364:1493–1502. doi: 10.1056/NEJMoa1102077. [DOI] [PubMed] [Google Scholar]
  • [23].Hao J, Campagnolo D, Liu R, Piao W, Shi S, Hu B, et al. Interleukin-2/interleukin-2 antibody therapy induces target organ natural killer cells that inhibit central nervous system inflammation. Ann Neurol. 2011;69:721–734. doi: 10.1002/ana.22339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [24].Yu J, Mao HC, Wei M, Hughes T, Zhang J, Park IK, et al. CD94 surface density identifies a functional intermediary between the CD56bright and CD56dim human NK-cell subsets. Blood. 2010;115:274–281. doi: 10.1182/blood-2009-04-215491. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [25].Jennett B, Snoek J, Bond MR, Brooks N. Disability after severe head injury: observations on the use of the Glasgow Outcome Scale. J Neurol Neurosurg Psychiatry. 1981;44:285–293. doi: 10.1136/jnnp.44.4.285. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [26].Kelly DF, Gonzalo IT, Cohan P, Berman N, Swerdloff R, Wang C. Hypopituitarism following traumatic brain injury and aneurysmal subarachnoid hemorrhage: a preliminary report. J Neurosurg. 2000;93:743–752. doi: 10.3171/jns.2000.93.5.0743. [DOI] [PubMed] [Google Scholar]
  • [27].Shi QG, Wang ZH, Ma XW, Zhang DQ, Yang CS, Shi FD, et al. Clinical significance of detection of antibodies to fetal and adult acetylcholine receptors in myasthenia gravis. Neurosci Bull. 2012;28:469–474. doi: 10.1007/s12264-012-1256-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [28].Lunemann A, Lunemann JD, Roberts S, Messmer B, Barreira da Silva R, Raine CS, et al. Human NK cells kill resting but not activated microglia via NKG2D- and NKp46-mediated recognition. J Immunol. 2008;181:6170–6177. doi: 10.4049/jimmunol.181.9.6170. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [29].Trinchieri G. Biology of natural killer cells. Adv Immunol. 1989;47:187–376. doi: 10.1016/S0065-2776(08)60664-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [30].Shi FD, Zhou Q. Natural killer cells as indispensable players and therapeutic targets in autoimmunity. Autoimmunity. 2011;44:3–10. doi: 10.3109/08916931003782122. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [31].Sun JC, Beilke JN, Lanier LL. Adaptive immune features of natural killer cells. Nature. 2009;457:557–561. doi: 10.1038/nature07665. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [32].Liu R, Van Kaer L, La Cava A, Price M, Campagnolo DI, Collins M, et al. Autoreactive T cells mediate NK cell degeneration in autoimmune disease. J Immunol. 2006;176:5247–5254. doi: 10.4049/jimmunol.176.9.5247. [DOI] [PubMed] [Google Scholar]
  • [33].Narayan RK, Michel ME, Ansell B, Baethmann A, Biegon A, Bracken MB, et al. Clinical trials in head injury. J Neurotrauma. 2002;19:503–557. doi: 10.1089/089771502753754037. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [34].Annane D, Meduri GU, Marik P. Critical illness-related corticosteroid insufficiency and community-acquired pneumonia: back to the future! Eur Respir J. 2008;31:1150–1152. doi: 10.1183/09031936.00040908. [DOI] [PubMed] [Google Scholar]
  • [35].Mavoungou E. Interactions between natural killer cells, cortisol and prolactin in malaria during pregnancy. Clin Med Res. 2006;4:33–41. doi: 10.3121/cmr.4.1.33. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [36].Masera R, Gatti G, Sartori ML, Carignola R, Salvadori A, Magro E, et al. Involvement of Ca2+-dependent pathways in the inhibition of human natural killer (NK) cell activity by cortisol. Immunopharmacology. 1989;18:11–22. doi: 10.1016/0162-3109(89)90026-X. [DOI] [PubMed] [Google Scholar]
  • [37].Mavoungou E, Bouyou-Akotet MK, Kremsner PG. Effects of prolactin and cortisol on natural killer (NK) cell surface expression and function of human natural cytotoxicity receptors (NKp46, NKp44 and NKp30) Clin Exp Immunol. 2005;139:287–296. doi: 10.1111/j.1365-2249.2004.02686.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [38].Hsueh CM, Chen SF, Lin RJ, Chao HJ. Cholinergic and serotonergic activities are required in triggering conditioned NK cell response. J Neuroimmunol. 2002;123:102–111. doi: 10.1016/S0165-5728(01)00488-X. [DOI] [PubMed] [Google Scholar]
  • [39].Prass K, Meisel C, Hoflich C, Braun J, Halle E, Wolf T, et al. Stroke-induced immunodeficiency promotes spontaneous bacterial infections and is mediated by sympathetic activation reversal by poststroke T helper cell type 1-like immunostimulation. J Exp Med. 2003;198:725–736. doi: 10.1084/jem.20021098. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [40].Jurkowski M, Trojniar W, Borman A, Ciepielewski Z, Siemion D, Tokarski J. Peripheral blood natural killer cell cytotoxicity after damage to the limbic system in the rat. Brain Behav Immun. 2001;15:93–113. doi: 10.1006/brbi.2000.0602. [DOI] [PubMed] [Google Scholar]
  • [41].Shi FD, Piao WH, Kuo YP, Campagnolo DI, Vollmer TL, Lukas RJ. Nicotinic attenuation of central nervous system inflammation and autoimmunity. J Immunol. 2009;182:1730–1739. doi: 10.4049/jimmunol.182.3.1730. [DOI] [PubMed] [Google Scholar]

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